Process for the preparation of pregnane derivatives

ABSTRACT

17 Beta -Hydroxy-17 Alpha -ethynyl steroids are converted to 17-ethers and 17-esters of 17 Alpha -hydroxy-20-keto-pregnane steroids by forming a 17-sulfite ester of the 17 Beta -hydroxy group with thionyl chloride in the presence of base and then reacting the sulfite ester with an alcohol or carboxylic acid in the presence of an Hg salt.

United States Patent [191 Berndt et al.

11] 3,741,997 [4 1 June 26, 1973 PROCESS FOR THE PREPARATION OF PREGNANE DERIVATIVES [75] Inventors: Hans-Dede! Berndt; Rudolf Wiechert, both of Berlin, Germany [73] Assignee: scheri'ng, A.G., Berlin, Germany [22] Filed: May 4, 1971 [21] Appl. No.: 140,262

[30] Foreign Application Priority Data May S, 1970 Gennany P 20 23 122.5

[52] U.S. CI. 260/397.4, 260/397.5 [51] Int. Cl. C07c 167/00, C07c 169/00 [58] Field of Search 260/397.4, 397.5

[56] References Cited UNITED STATES PATENTS 3,465,009 9/1969 Teller et al. 260/397.4

3,485,852 12/1969 Ringold et al. 260/397L4 Primary Examiner-Elbert L. Roberts Attorney-Millen, Raptes & White 57 ABSTRACT 30 Clainis, No Drawings PROCESS FOR THE PREPARATION OF PREGNANE DERIVATIVES BACKGROUND OF THE INVENTION This invention relates to a process for the preparation of riregnane derivatives, more particularly l7-ethers and esters of l701-hydroxy-20-keto pregnane steroids and to novel sulfite esters and a process for their production.

The process of this invention is a method for converting l7B-hydroxy-l7a-ethinyl steroids into l 7a-oxy-20- keto pregnanes. Such methods are known per se (J. Amer. Chem. Soc. 89,1967, 5505; as well as J. Org. Chem. 33, 1968, 3294). However, these methods are unsuitable for the commercial production of such pregnane steroids, in part because too many reaction steps are required in part because the individual reaction steps are too expensive for a commercial process.

It is an object of this invention to provide a novel process for the conversion of l7a-ethynyl-l7/3-hydroxy steroids to l7-ethers and esters of l7a-hydroxy-20- keto pregnane steroids. It is another object of this invention to provide novel sulfite esters of Formula III and a process for the preparation ofthese sulfite esters. Other objects will be apparent to those skilled in the art to which this invention pertains.

SUMMARY OF THE INVENTION According to this invention, a l7a-ethynyl-l7l3- hydroxy steroid is converted with thionyl chloride in the presence of base into a l7-bis-sulfite ester, which is then converted with an alcohol or acid in the presence of an Hg salt into a l7-ether orl7-ester, respectively, of a l7a-hydroxy-20-keto pregnane series steroid.

DETAILED DISCUSSION The process of this invention can be illustrated in its generic aspects by the following reaction scheme:

/OH Soc} S0 /COCH3 St St St base R OI'I CECH CECH 2 OR:

I II III whe rein St is a steroidal cyclopentanopolyhydrophenanthrene nucleus bearing the substituents shown in the formulae on its C carbon atom, and R OH is an alcohol or a carboxylic acid. In its preferred aspect, the

wherein D signifies the D ring of a cyclopentanopolyhydrophenanthrene nucleus and R, has the value given below and R has the value given above.

The steroid nucleus can bear the usual substituents on any or all of its rings, including hydroxy, keto, halo, especially fluoro, oxido, alkyl especially methyl, hydrocarbonoxy, especially lower-alkoxy and benzyloxy, acyloxy, especially lower-alkanoyloxy, e. g., at the l, 2, 3, 4, 5, 6, 7, 8,9, 11,12, 14,15 and 16 positions. Either or both of the angular methyl groups at the lOand 13 positions can be present or absent or replaced by higher alkyl, preferably ethyl. The stereoconfiguration can be that of the natural steroids or 8-iso or a racemic mixture of the D- and L- stereoisomers.

The process of this invention is a two-step method of converting l7B-hydroxy-l7u-ethynyl steroids to 1-7- ethers and esters of l7a-hydroxy-20-keto steroids of the pregnane series. A wide variety of these steroids are known. For example, in the substituted and unsubstituted progesterone series, many l7-esters are known which are orally active as anti-fertility compounds. In the substituted and unsubstituted cortisone, hyd'rocortisone, prednisone and prednisolone series, such- 17- esters are known to possess topical anti-inflammatory activity. It will be apparent to those skilled in the art' that the pharmacological acitvity of the products of the process of this invention will be dictated by the substituents present in, e.g., the 2, 3, 4, 5, 6, 7, 9 and/or 1 l-' positions according to well-established structureactivity relationships.

For example, the l 7/3-hydroxy-l70z-ethinyl: steroids employed as the starting compounds for the process of this invention can bear as substituents an etherifie d or esterified hydroxy group in the 1-, 3-, 6- and/or llposition; a keto group in the 3- and/or ll-position; a fluorine atom.-in the 2-, 4-, 6- and/or 9 position; a methyl group in the 1-, 2-. and/or -position; and/or a methylene group in the l,2a-, 5,10aand/orbflgposition.

The starting materials can have one or more double bonds in the molecule, for example, in the 1-, 3-, 4-, 5(6)-, 5( l0)-, or 9(1 l)-position. Also, the A-ring and- /or B-ring can be aromatic.

The process of this invention is preferably employed as part of a total steroid synthesis. Therefore, preferred starting compounds for the process are l7B-hydroxy-' wherein R is methyl or ethyl. and A is one of the following groups:

V formyl, acetyl, propionyl, butyryl, or benzoyl.

' As will be apparent to those skilled in the art, the preferred sulfite esters of Formula II and Formula Ila and the preferred l7a-oxy-20-keto pregnanes of Formula III and Formula llla will also possess the steroid nucleus of .the compounds of Formula IV.

The process of this invention is a two-stage process. In the. first stage, a l7/3-hydroxy-l 7a-ethinylsteroid of the general Formula II is converted with thionyl chloride, in the presence of a base, into a bis-sulfite ester, e.g., of the Formula II.

, Suitable bases for conducting the first stage of the .process of'this invention. .are the organic bases which are customarily employed as basic catalysts for esterifi cation reactions withcarboxylic acid chlorides. Such bases are well known to those skilled in the art. Particularly's'uitable bases are the aromatic tertiary N- heterocyclic amines, e.g., pyridine, c'ollidine, lutidine,

-. quino'line, and ,quinaldine.

The organic base can additionally be diluted with an inert organic solvent. Examples of such solvents are methylene chloride, chloroform, ethylene chloride, dioxane, tetrahydrofuran, benzene, toluene, dimethylformamide and dimethyl sulfoxide.

In order to obtain high yields in the sulfite ester of general Formula lI,-it is advantageous to conduct the reaction at a low temperature, i.e., below room temperature, preferably. below C. Very high yields in sulfite ester can be obtained by effecting the reaction at a'temperature of between about C'. and about 80 C preferably about 30 C. to 70 C.

It was surprising that bis sulfite esters were produced by the reaction of l7B-hydroxy-l7a-ethinyl steroids with thionyl chloride because it is known that, when thionyl chloride is reacted with other steroids bearing tertiary hydroxyl groups, water is readily split off. Consequently, it would be expected that reacting thionyl chloride with l7B-hydroxy-l7a-ethinyl steroids would produce as the reaction product the corresponding l7- ethinyl-A' -steroids, instead of a bis-sulfite ester.

The thus-produced bis-sulfite esters, in addition to being intermediates for the production of the l7-oxy- 20-keto pregnanes of Formulae Ill and Illa, possess bacteriostaticactivity and, by virtue of the sulfite ester group, are mild reducing agents comparable to dialkylsulfites.

In the second reaction of the process of this invention,=thersulfitea=ester produced in the first step is reacted, in the presence ofa mercury (ll) salt, with an alcohol or a carboxylic acid.

Examples of carboxylic acids which can be-employed are aliphatic, araliphatic and aromatic carboxylic acids containing perferably l to 8 carbon atoms, e.g., formic, acetic, propionic, butyric, valeric, hexanoic, octanoic, cyclopentylca'rboxylic, cyclopentylacetic, cyclohexylacetic, benzoic, 2-, 3-, or 4-methylbenzoic, and phenylacetic acid.

Examples of alcohols which can be employed are primary alkanols, containing preferably l4, carbon atoms, optionally substituted by phenyl, e.g., methanol, ethanol, n-propanol, n-butanol, and benzylalcohol'.

The reaction can, of course, be conducted in the presence of an inert reaction solvent as a diluent. Suitable solvents are, for example, polar aprotic solvents, e.g., dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dioxane and tetrahydrofuran. These solvents can be used alone, or in the presence of a non-polar solvent miscible therewith.

Particularly suitable as the mercury (II) salt for the 7 second reaction stage of the process of this invention are the mercury(ll) salts of organic carboxylic acids, preferably an aliphatic acid as defined hereinafter,

more preferably those containing 1-8 carbon atoms,

e.g., mercury(ll) formate and mercury(") acetate. If a carboxylic acid is employed as the reactant in the sec-. ond reaction, the mercury( II) salts can be produced by reacting mercury( ll) oxide with the selected carboxylic acid. i

The second reaction of the process of this invention can be conducted at room temperature or at an elevated temperature. Preferably, the reaction is conducted at a reaction temperature of between about 0 C. and C. The product of the reaction in the second stage of the process of this invention is also surprising. Although one skilled in the art knows that corresponding ketones can be producedby reacting acetylene compounds with water, alcohols, or acids in the presence of mercury(") salts, it could not be predicted that the l7B-positioned hydroxyl group and the l7otpositioned side chain of the sulfite esters of Formula II would be subjected to inversion during the course of the reaction, and the desired pregnane derivatives with a B-positioned side chain would thus be formed.

Preferred R groups for the pregnane derivatives of Formula Ill and Formula Illa when R,O- is an ether group are those wherein R, is hydrocarbon, e.g., of l-8 carbon atoms, preferably lower-alkyl, i.e., containing 1-4 carbon atoms, optionally substituted by phenyl. Specific examples are ethyl, n-propyl, n-butyl, and benzyl. Preferred acyl R, groups are acyl radicals of car boxylic acids containing l-8 carbonatoms, e.g., formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, and benzoyl.

The preferred alcohols and carboxylic acids employed in the second step of the process of this invention to produce the pregnanes of Formula Ill and F ormula Illa are preferably those of the formula R, wherein R, is the preferred group. Especially preferred are methanol, ethanol and benzyl alcohol and'formic acid and acetic acid.

Since it is possible, by the process of this invention, to prepare pregnane derivatives from 17- oxoandrostanes and l7-oxoestranes by a three-stage synthesis (the first being ethynylation) which technically is easy to conduct, this invention is particularly valuable as part of a partial or total synthesis of pregnane compounds, for example, gestagenically active l7a-hydroxyprogesterone derivatives, e.g., l 7a-hydroxyprogesterone caproate, l7a-hydroxyl 9- norprogesterone caproate, l7a-benzyloxyl 9-nor-4- pregnene-3, 20-dione and chlormadinone, and corticolds. having an antiphlogistic effect, e.g., hydrocortisone, prednisolone, triamcinolone and dexamethasone.

Without further elaboration. it is believed that one skilled in the art can, using the preceding description. utilize the present invention to its fullest extent. The

following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

EXAMPLE l Forty g. of 17 B-hydroxy-l7a-ethinyl-4-androsten- 3-one is dissolved in 400 ml. of methylene chloride and 1500 ml. of pyridine. The solution is cooled'to 60 C then, 40 ml. of thionyl chloride is gradually added dropwise. After maintaining the reaction solution at -60 C. for l hour, the reaction product is precipitated in water and then taken up in methylene chloride. The organic phase is washed successively with dilute hydrochloricacid, water, aqueous sodium bicarbonate solution, and water, then dried with sodium sulfate, and concentrated to dryness under vacuum. The residue is triturated and extracted for 1 hour with 1 liter of ethyl acetate. The suspension is allowed to cool, theprecipitate is filtered off, recrystallized from ethanol, and thus 36 g. of bis(3-oxo-l7a-ethinyl-4-androsten-l7B-yl) sulfite is obtained, m.p. 2032041C. (decomposition).

EXAMPLE 2 3/3-Acetoxy-l8-methyl-i7a-ethinyl-5B, l9-cycloandrostan-l7B-ol (2 g.; m.p. l40-l42 C.) is dissolved in 40 ml. of methylene chloride and 40 ml. of pyridine and mixed with 2 ml. of thionyl chloride at 50 C. After minutes at -50 C., the reaction product is precipitated in water and taken up in methylene chloride. The solution is washed with water, dried over sodium sulfate, and evaporated to drynessunder vacuum. The residue of theevaporation step is chromatographed on 100 g. of silica gel. After gradient elution with hexane/25 percent strength ethyl acetate, 1.79 g. of l9'-cycloandrostan-l7B-yl) sulfite is obtained. After bis(3B-acetoxy-l 8-methyll 7a-ethinyl-5B,

crystallization from hexane/acetone, the compound melts at 178 -179" C. (decomposition).

EXAMPLE 3 gradient elution with hexane/25 percent strength ethyl acetate and crystallization from ethyl acetate, 1.2 g. of

-bis(3-oxo-l7a-ethinyl 4-estren-l7B-yl) sulfite is'" obtained, m.p. l88l89 (decomposition).

' EXAMPLE 4 Twenty g. of .l 7B-hydroxyl 8-m ethyll 7a-eihinyl-4- estren-3-one is taken up in 200 ml. of methylene chloride and 750 ml. of pyridine. and the solution is cooled to -70 C. Within 30 minutes, 20 ml. of thionyl chloj I g eFifty, mg.-of'mercuric.oxide, yellow, is dissolved in 5 'ml. of 85 percenuof formic acid and mixed with 1 g. of

ride is added dropwise' to the reaction solution After 90 minutes at ---70 C., the reactionproduct isprecipitated in ice water. and taken up in methylene chloride. The organic phase is washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution, and water, dried over-sodium sulfate. and concentrated to dryness undervacuum. The residue of the evaporation step is chromatographed on silica gel. After gradient elution with hexane/30 percent strength ethyl acetate, 15 g.. of -bis(3-oxo-l8-methyl-l7aethinyl-4-estren-l7B-yl)sulfite is obtainedyfrom diisopropyl ether/methylene chloride: m.p. l63-l64 C. (decomposition); from ethanol: m.p. l56-l 57 C. (decomposition). I

EXAMPLE 5 Sixg. of 3-acetoxy-b 17a-ethinyl-l,3, 5( l0) estratrien-l7B-ol is mixed, in 225 ml. of pyridine and 60 ml. of methylene chloride, with 6 ml. of'thionyl chloride at C. After 1 hour at 70 C., the reaction product is precipitated in ice water. The solution is washed successively with dilute hydrochloric acid, .water, aqueous sodium bicarbonate solution. and water, dried with sodium sulfate, and concentrated to dryness under vacuum. After recrystallization from ethanol, 3.5 g. of bis- (3-acetoxy-l7a-ethinyl-l ,3 ,5( l0 )-estratrienl 7B-yl) sulfite is obtained, m.p. l84-l85 C.

EXAMPLE 6 Six hundred and seventy mg. of bis(3-oxo-l7aethinyl-4-androsten-l7fi-yl) sulfite is dissolved in 350 ml. of methanol, and the solution is mixed at room'temtrated under vacuum. After crystallizing the residue of the evaporation step from hexane/acetone, 525 mg. of 'l7a-methoxy-4-pregnene-3,ZO-dione is obtained having the melting point of 205-207 C.

EXAMPLE 7 3.35 g. of bis(3-oxo-l 7a-ethinyl-4-androstenl 7B-yl) sulfite is dissolved in 200 ml. of- N,N-

dimethylacetamide and 400 ml. of glacial acetic acid and mixed with 3.2 g. of mercury-(ll) acetate and 2 ml. of water. After 16 hours at room temperature, the mercury is precipitated with aqueous sodium sulfide solution, and the thus-produced mercury sulfide sediment is filtered off over Celite (or the reaction solution is adjusted to a pH of 10 with aqueous sodium hydroxide solution, and the mercury is bound with Complexon). The reaction product is taken up in methylene chloride, and the organic phase is washed three times with water, dried with sodium sulfate, and concentrated to dryness under vacuum. The evaporation residue is chromatographed on 300 g. of silica 'gel, thus obtaining, after gradient elution with hxane/SO petcent strength ethylacetate, 1.0 g. of l7a-acetoxyprogi esterone,

' From hexane/acetone: m.p. 237240 C.

EXAMPLE 8 bis( 3/3-'acetoxy- -l 8-.methyl- 1 7a-ethinyl-5B,'l 9-' cycloandrostan-l7B-yl) sulfite in. 5 ml. of tetrahydro- EXAMPLE 9 Ten g. of l7B-hydroxy-l8-methyl-l7a-ethinyl-4- androsten-3-one is reacted, as described in Example 1, in 100 ml. of methylene chloride and 100 ml. of pyridine, with 10 ml. of thionyl chloride at 60 C.

After the reaction mixture has been worked up and recrystallized from ethanol, 7.8 g. of bis(3-oxo-l8- methyl-l7a-ethinyl-4-androsten-l7B-yl) sulfite is obtained.

EXAMPLE l 1.] g. of bis(3-oxo-l7aethinyl-4-estren-l7B-yl) sulfite is mixed with 20 ml. of benzyl alcohol, 2.l g. of mercury(ll) acetate, and 8 ml. of water and heated, under a nitrogen atmosphere, to 30 C. for 20 hours.

After working up the reaction mixture as described in Example 7, l7a-benzyloxy-l9-nor-4-pregnene-3,20- dione is obtained in the form of a colorless oil. [e1 15,200.

EXAMPLE 1 l 0.63 g. of bis(3-oxo-l7a-ethinyl-4-estren-17B-yl) sulfite is mixed with ml. of acetic anhydride, 30 ml. of formic acid, and 30 ml. of dimethylformamide, and the mixture is cooled to +l0 C. Then, 500 mg. of mercury(ll) acetate is added to the reaction mixture, and the latter is agitated for 3 hours at +10 C.

After the reaction mixture has been worked up as described in Example 8, 400 mg. of l7a-formyloxy-l9- nor-4-pregnene-3,20-dione is obtained, m.p. l95l97 The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

l. A process for the production of l7-ethers and esters of l7a-hydroxy-20-keto steroids which comprises the steps of reacting a l7B-hydroxy-l7a-ethynyl stemid of the formula wherein St is a cyclopentano-polyhydrophenanthrene nucleus bearing the substituents shown in the formula on its C carbon atom, with thionyl chloride in the presence ofa base to form a sulfite bis-ester of the 17B- hydroxy group and reacting the thus-produced sulfite bis-ester with a primary or secondary alcohol or carboxylic acid capable of forming ethers and esters, respectively, in the presence of an Hg salt.

2.1A process according to claim 1 wherein the starting steroid bears an angular methyl or ethyl group at the l8-position.

3. A process according to claim 1 wherein the sulfite bis-ester is reacted with a lower-alkanoic acid.

4. A process accordingto claim 1 wherein the sulfite bis-ester is reacted wtih a hydrocarbon primary alcohol.

5. A process'according to claim 1 wherein the sulfite bis-ester is reacted with methanol, ethanol, formic acid or acetic acid.

6. A process according to claim I wherein the sulfite bis-ester is reacted with benzyl alcohol.

7. A process according to claim I wherein the base is pyridine.

8. A process according to claim 1 wherein the reaction with thionyl chloride is conducted at about 30 C. to about C.

9. A process according to claim 1 wherein the mercury(ll) salt is mercury(ll) formate or mercury(ll) acetate.

10. A process according to claim 1 wherein the starting l7B-hydroxy-l 7a-ethiny1 steroid has the formula wherein R is methyl or ethyl and A is one of the groups .OQQ

12. A process according to claim 11 wherein the sulfite bis-ester is reacted with methanol, ethanol, formic acid or acetic acid.

13. A process according to claim 11 wherein the sulfite bis-ester is reacted with benzyl alcohol.

14. A process for the production of a bis-steroidal sulfite ester which comprises reacting a l7B-hydroxyl7a-ethynyl steroid ofthe formula I wherein St is a cyclopentano-polyhydrophenanthrene nucleus bearing the substituents shown in the formula on its C carbon atom, with thionyl'chloride in the presence ofa base to form a bis sulfite ester of the 178- hydroxy group. 15. A process according to claim 14 wherein the base is pyridine.

16. A process according to claim 14 wherein the reaction is conducted at about "30 C. to about 70 C. 17. A process according'to claim 14 wherein the base is pyridine and wherein the reaction is conducted at about 30 C. to about 70 C. I 18. A l7-bis sulfite ester of a l7B-hydroxy-l7aethynyl steroid of the formula so SP J 0501; 2

wherein St is a steroidal cyclopentanopolyhydrophenanthr'ene nucleus bearing the substituents shown in the above formula on its C carbon atom, said nucleus having the formula wherein R is methyl or ethyl and A is one of the groups or a we ily I wherein R is a hydrogen atom or methyl,- R and R each are a hydrogen atom, alkyl or acyl, and R is alkyl or acyl.

19. A compound of claim 18, bis(3-ace toxy-l7ozethinyl-l .3,5( lO)-estratrien-l 7B yl) sulfite.'

20. A compound of claim 18, bis(3-oxo-l8-methyll7a-ethinyl-4-estren-l7B yl) sulfite. I

21. A compound of claim 18. bis (3-oxo-l 7a-ethinyl- 4-estrenl 7B-yl) sulfite.

22. A compound of claim 18, bis (3B-acetoxy-l8- s. J c5011 2 wherein St is a cyclopentano-polyhydrophenanthrene nucleus bearing the substituents shown in the formula on its C carbon atom, with a primary or secondary a1- cohol or a carboxylic acid in the presence of an l'lg salt.

27. .A process according to claim 27 wherein the l-lg salt is a salt of an aliphatic acid containing 1-8 carbon atoms. g

28. A process according to claim 27 wherein the Hg salt is mercuryfll) formate or acetate.

29. l7a-Formyloxy-3fi-acetoxy-18-methyl-5B,l9-

cyclopregnane-20-one.

30. A'bis-su'lfite ester according to claim 18 of the formula R1 |....C:OH g

wherein R, is methyl or ethyl and A is one of the following groups:

wherein R is a hydrogen atom or methyl, R and R each are a hydrogen atom, alkyl of l-4 carbon atoms. benzyl or alkanoyl of l-8 carbon atoms and R, is alkyl of 1-4 carbon atoms or alkanoyl of l-8 carbon atoms. 

2. A process according to claim 1 wherein the starting steroid bears an angular methyl or ethyl group at the 18-position.
 3. A process according to claim 1 wherein the sulfite bis-ester is reacted with a lower-alkanoic acid.
 4. A process according to claim 1 wherein the sulfite bis-ester is reacted wtih a hydrocarbon primary alcohol.
 5. A process according to claim 1 wherein the sulfite bis-ester is reacted with methanol, ethanol, formic acid or acetic acid.
 6. A process according to claim 1 wherein the sulfite bis-ester is reacted with benzyl alcohol.
 7. A process according to claim 1 wherein the base is pyridine.
 8. A process according to claim 1 wherein the reaction with thionyl chloride is conducted at about -30* C. to about -70* C.
 9. A process according to claim 1 wherein the mercury(II) salt is mercury(II) formate or mercury(II) acetate.
 10. A process according to claim 1 wherein the starting 17 Beta -hydroxy-17 Alpha -ethinyl steroid has the formula
 11. A process according to claim 1 wherein the starting steroid has an angular methyl or ethyl group at the 18-position; the sulfite bis-ester is reacted with a lower-alkanoic acid or with a hydrocarbon primary alcohol; the base is pyridine; the reaction with thionyl chloride is conducted at about -30* C. to about -70* C; and the mercury(II) salt is mercury(II) formate or mercury(II) acetate.
 12. A process according to claim 11 wherein the sulfite bis-ester is reacted with methanol, ethanol, formic acid or acetic acid.
 13. A process according to claim 11 wherein the sulfite bis-ester is reacted with benzyl alcohol.
 14. A process for the production of a bis-steroidal sulfite ester which comprises reacting a 17 Beta -hydroxy-17 Alpha -ethynyl steroid of the formula
 15. A process according to claim 14 wherein the base is pyridine.
 16. A process according to claim 14 wherein the reaction is conducted at about -30* C. to about -70* C.
 17. A process according to claim 14 wherein the base is pyridine and wherein the reaction is conducted at about -30* C. to about -70* C.
 18. A 17-bis-sulfite ester of a 17 Beta -hydroxy-17 Alpha -ethynyl steroid of the formula
 19. A compound of claim 18, bis(3-acetoxy-17 Alpha -ethinyl-1,3, 5(10)-estratrien-17 Beta -yl) sulfite.
 20. A compound of claim 18, bis(3-oxo-18-methyl-17 Alpha -ethinyl-4-estren-17 Beta -yl) sulfite.
 21. A compound of claim 18, bis (3-oxo-17 Alpha -ethinyl-4-estren-17 Beta -yl) sulfite.
 22. A compound of claim 18, bis (3 Beta -acetoxy-18-methyl-17 Alpha -ethinyl-5 Beta ,19-cycloandrostan-17 Beta -yl) sulfite.
 23. A compound of claim 18, bis(3-oxo-17 Alpha -ethinyl-4-androsten-17 Beta -yl) sulfite.
 24. A compound of claim 18, bis(3 Beta -acetoxy-18-methyl-17 Alpha -ethinyl-5 Beta ,19-cycloandrostan-17 Beta -yl)sulfite.
 25. A compound of claim 18, bis(3-oxo-18-methyl-17 Alpha -ethinyl-4-androsten-17 Beta -yl) sulfite.
 26. A process for the production of 17 Alpha -ethers and 17 Alpha -esters of 20-keto steroids of the pregnane series which comprises reacting a 17-bis-sulfite ester of a 17 Beta -hydroxy-17 Alpha -ethynyl steroid of the formula
 27. A process according to claim 27 wherein the Hg salt is a salt of an aliphatic acid containing 1-8 carbon atoms.
 28. A process according to claim 27 wherein the Hg salt is mercury(II) formate or acetate.
 29. 17 Alpha -Formyloxy-3 Beta -acetoxy-18-methyl-5 Beta ,19-cyclopregnane-20-one.
 30. A bis-sulfite ester according to claim 18 of the formula 